Shah et al.

BMC Pediatrics 2014, 14:110

http://www.biomedcentral.com/1471-2431/14/110

STUDY PROTOCOL Open Access

The International Network for Evaluating

Outcomes of very low birth weight, very preterm
neonates (iNeo): a protocol for collaborative
comparisons of international health services for
quality improvement in neonatal care
Prakesh S Shah1*, Shoo K Lee1, Kei Lui2, Gunnar Sjrs3, Rintaro Mori4, Brian Reichman5, Stellan Hkansson6,
Laura San Feliciano7, Neena Modi8, Mark Adams9, Brian Darlow10, Masanori Fujimura11, Satoshi Kusuda12,
Ross Haslam13, Lucia Mirea1 and on behalf of the International Network for Evaluating Outcomes of Neonates
(iNeo)

Abstract
Background: The International Network for Evaluating Outcomes in Neonates (iNeo) is a collaboration of
population-based national neonatal networks including Australia and New Zealand, Canada, Israel, Japan, Spain,
Sweden, Switzerland, and the UK. The aim of iNeo is to provide a platform for comparative evaluation of outcomes
of very preterm and very low birth weight neonates at the national, site, and individual level to generate evidence
for improvement of outcomes in these infants.
Methods/design: Individual-level data from each iNeo network will be used for comparative analysis of neonatal
outcomes between networks. Variations in outcomes will be identified and disseminated to generate hypotheses
regarding factors impacting outcome variation. Detailed information on physical and environmental factors, human
and resource factors, and processes of care will be collected from network sites, and tested for association with
neonatal outcomes. Subsequently, changes in identified practices that may influence the variations in outcomes will
be implemented and evaluated using quality improvement methods.
Discussion: The evidence obtained using the iNeo platform will enable clinical teams from member networks to
identify, implement, and evaluate practice and service provision changes aimed at improving the care and
outcomes of very low birth weight and very preterm infants within their respective countries. The knowledge
generated will be available worldwide with a likely global impact.
Keywords: Very preterm infants, Very low birth weight infants, Neonatal intensive care unit, Neonatal networks,
Comparative analysis, Neonates, Quality improvement

* Correspondence: pshah@mtsinai.on.ca
1
Canadian Neonatal Network, Maternal-Infant Care Research Centre, Mount
Sinai Hospital, 700 University Avenue, Toronto, Ontario M5G 1X6, Canada
Full list of author information is available at the end of the article

2014 Shah et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Shah et al. BMC Pediatrics 2014, 14:110
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Background
The global incidence of preterm birth is on the rise [1]. In
Canada the incidence of preterm birth (<37 weeks gesta-
tional age) has increased from 6.3% in 1981 to 7.7% in 2009
[2,3]. Although infants born at a very low birth weight
(VLBW, <1500 g) and/or very preterm (VPT, <32 weeks
gestational age) make up only 14% of all preterm births
in Canada [3], they are of significant public health
importance due to their high risk of mortality and child-
hood morbidities. These morbidities include developmen-
tal problems, cerebral palsy, cognitive delay, blindness,
and deafness [4,5], with an estimated lifetime cost of
CAD$676,800 per preterm infant with permanent dis-
ability [6]. Therefore, it is important to identify strat-
egies that will reduce the risk of adverse outcomes
suffered by VLBW and VPT infants and improve quality
of life for these infants.
Various national neonatal networks, such as the
Australia-New Zealand Neonatal Network (ANZNN)
[7], Canadian Neonatal Network (CNN) [8], Israeli Neo-
natal Network (INN) [9], Neonatal Research Network of
Japan (NRNJ) [10], Swedish Neonatal Quality Register
(SNQ) [11], and UK Neonatal Collaborative (UKNC)
[12], have been established to collect data from their
constituents and identify trends in the outcomes of
VLBW infants and benchmark the performance of their
respective centers. Although advances in neonatal care
between the 1960s and the 1990s resulted in significant
reductions in mortality and morbidity for neonates
[13-16], recently some networks, including the CNN,
have observed a halt in progress or even worsening of
outcomes [13,17-19].
Even for those neonatal networks where continued im-
provements in outcomes have been reported, there re-
mains significant variation within and between networks.
For example, several comparative studies have identified
differences in mortality rates in neonates from separate
networks, regions, or countries [20-27]. In one such
study, Draper et al. reported that among 10 European
regions, the overall survival rate for VPT infants varied
from 74.8% to 93.2% [21]. More recently, in 2012 popula-
tion data from the UKNC showed a greater than three-
fold variation between regional networks in the percentage
(range 4.7% to 16.6%) of infants born at <30 weeks ges-
tation and admitted to neonatal units who died at 28 days
of age [27]. Comparison of selected Australian and Scottish
neonatal intensive care units (NICUs) detected a lower
risk-adjusted mortality rate for VPT/VLBW infants in
Australia compared with Scotland [28].
However, studies of a single or small group of sites are
subject to selection bias, which can lead to erroneous
conclusions when the results are generalized to the lar-
ger population. Furthermore, comparisons of mortality
alone may be misleading as mortality may be declining
Page 2 of 11
at the cost of increasing morbidities. Measurement of
mortality as an indicator of care is also a contentious
issue as there are marked variations in practice between
countries including initiation or withholding of resusci-
tation at earlier gestational ages [29]. Thus, this protocol
for the International Network for Evaluating Outcomes
of Neonates (iNeo) was developed to examine neo-
natal morbidities in conjunction with mortality using
population-based data, and assess variations in practice
that impact outcomes between and within countries.
Rationale
Over the past 5 years, collaborations have been initiated
between the CNN, NRNJ, ANZNN, and SNQ. The first
ever population-based retrospective comparison between
countries showed that a composite outcome of mortality
or any major morbidity (bronchopulmonary dysplasia
[BPD], severe neurological injury, stage 3 retinopathy
of prematurity [ROP], nosocomial infection [NI], and
stage 2 necrotizing enterocolitis [NEC]) was lower in
VLBW infants in Japan compared with Canada. In-depth
analyses revealed higher rates of severe neurological in-
jury, NEC, and NI among NICUs in the CNN, whereas
rates of BPD and ROP were higher in NRNJ NICUs [30].
Comparisons between the CNN and the ANZNN for
VPT infants identified that while there was no difference
in mortality, the ANZNN had significantly lower rates of
severe neurological injuries, ROP, NEC, and BPD, but
higher rates of early onset sepsis and air leaks and longer
mean length of stay [31,32]. Our latest comparisons indi-
cated that rates of adverse outcomes at each gestational
age were lower in Sweden compared with Canada (un-
published data).
Differences in the outcomes of VLBW and VPT in-
fants between Canada and other countries could be due
to any number of factors including differences in popu-
lation characteristics, severity of illness, processes of
care, or delivery of health care. Informal discussion has
confirmed wide variations in these factors between net-
works. For example, compared with Canada, the use of
non-invasive respiratory support is higher in Europe, the
use of breast milk is higher in Japan and Scandinavia,
and the use of echocardiography by neonatologists for
hemodynamic monitoring is routine in Japan. Differ-
ences in the type of intervention and process of adminis-
tration may underlie at least some of the variations in
outcomes. In addition, there are extreme variations in
health services delivery and receipt. For example, the
number of outborn, very preterm infants is significantly
lower in the ANZNN compared with the CNN [32]; the
use of respiratory therapists is practically non-existent in
European countries, whereas they play a prominent role
in North American institutions; and shift work is more
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prevalent among junior doctors in Europe and Australia
[33] compared with Canada.
Given the variation in mortality and morbidity be-
tween countries, it is important to first characterize fac-
tors underlying these differences, and then identify areas
and approaches to improve neonatal care specific to
each network. Care provision to VLBW and VPT infants
is a highly selective health service where specialized
units deliver the majority of such care (approximately
80% of VLBW and VPT infants are admitted to tertiary
NICUs), and consumes extensive resources, both in
terms of the per-diem cost of caring for such a neonate
in the NICU and cumulative lifetime costs. To improve
outcomes and reduce health care costs globally, we need
to embrace the concept of collaborative sharing and
learning, assess the variation in practices between coun-
tries/networks, identify evidence-based practices associ-
ated with improved outcomes, and apply these practices
to deliver optimal health care to fragile neonates.
Currently, informal and indirect comparisons can be
made from the reports published by each national net-
work. However, criticisms of such indirect or post-hoc
comparisons include lack of adjustment for differences
in baseline infant and maternal characteristics, differ-
ences in definitions of outcomes and their measurement,
and variations in physical, environmental, and human
factors (e.g. training system and associated working con-
ditions of physicians on duty day and night, differences
in nursing care and nurse:beds ratio, differences in
regionalization system, and the rate of maternal transfer
for extremely preterm fetuses). A system of data
standardization and an understanding of the context for
comparison are urgently needed to enable valid compar-
isons between networks. This can only be achieved
through an international collaboration where the know-
ledge users and decision makers are involved from the
start of the process and continuously through to know-
ledge translation. Analyses of network-level data using
all eligible infants will provide a more accurate estimate
of the effectiveness of an intervention in a pragmatic set-
ting, rather than just a measure of efficacy proven in a
controlled study setting.
Network objectives
The specific aims of iNeo are to:
1. Compare outcomes for infants born with VLBW
(weighing <1500 g) and VPT (<32 weeks gestation)
among eight national neonatal networks spanning
nine countries.
2. Identify site-level physical, human, and
environmental characteristics, as well as care
practices that are associated with variations in
outcomes.
Page 3 of 11
3. Identify clinical and organizational practice
improvements relevant to each network.
4. Implement and continually evaluate the impact of
evidence-based clinical and organizational practice
changes in NICUs within the iNeo networks.
The establishment of the iNeo collaboration will en-
able the following: i) collection and integration of
individual-level data from population-based networks on
outcomes, characteristics, practices, and culture of the
member sites; ii) evaluation of the impact of practice
and outcome variations to identify the best models of
health service delivery (incorporating medical and other
extraneous factors); iii) feedback to units of their stand-
ing in reference to each and all other networks; iv)
empowerment of units to embrace implementation of
evidence-based practice changes for quality improve-
ment; and v) performance of ongoing cycles of translat-
ing knowledge-to-action through continuous auditing.
Ultimately, this will improve outcomes for VLBW in-
fants across the iNeo member networks.
Methods/design
Overview
The comparison of neonatal mortality and morbidity be-
tween the eight member networks will be conducted
using four years of retrospective data collected between
January, 2007 and December, 2010. Subsequently, a
strategy will be designed to collect additional data and
assess differences in physical, environmental, and human
characteristics, and care practices associated with varia-
tions in outcomes between networks. Once identified,
clinical and organizational practice improvements will
be implemented within networks using the Evidence-
based Practice for Quality Improvement (EPIQ) method
[34,35]. The effect of practice change implementation
will be measured using ongoing data collection within
each network. The total study period will be five years
(January 2013 to December 2017). Comparison between
the networks will be completed by early 2014, associa-
tions between external factors/care practices and out-
comes identified by the end of 2014, and selected
practice changes implemented by mid 2015. This will be
followed by a two and a half-year period of continuous
quality improvement within the networks.
Participating networks
The following neonatal networks have agreed to partici-
pate in the iNeo project: Australia-New Zealand Neonatal
Network (ANZNN), Canadian Neonatal Network (CNN),
Israeli Neonatal Network (INN), Neonatal Research
Network of Japan (NRNJ), Spanish Neonatal Network
(SEN1500), Swedish Neonatal Quality Register (SNQ),
Swiss Neonatal Network (SNN), and UK Neonatal
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Collaborative (UKNC) (see Table 1). Overall, this project
will be collecting data from a total of 251 NICUs in nine
countries caring for approximately 23,000 to 24,000
VLBW neonates per year. All the participating networks
have a common mandate to collect, analyze, and bench-
mark performance and outcomes of their respective
NICUs. We have carefully avoided networks that only in-
clude highly specialized units in order to obtain robust
population-based estimates. All participating networks
have confirmed the feasibility of data collection from
>75% of all VLBW and VPT infants born within their
country. The approximately 25% of infants missing from
some of the networks are those considered to be at the
higher end of maturity (>1300 g birth weight or >30 weeks
gestation) who do not require intensive care support.
These infants are relatively stable and do not represent a
significant burden to NICUs or health care services in
general.
Database variables
A detailed review of all the data items collected by each
of the participating networks has been conducted and
the elements common to all networks (e.g. gestational
age, birth weight, sex, etc.) included in a minimum data-
set (see Additional file 1 for full list of data variables).
Data items that are collected by all networks in slightly
different formats (e.g., nosocomial infection, which can
be defined by using a cut-off of 2 days, 3 days, or 7 days)
have been standardized across all the networks by con-
sensus of the network directors. Some networks already
extract data from their databases according to the iNeo
definitions, while others have agreed to redefine their
original data formats as an ongoing process to ensure
consistency and facilitate comparisons over time. The
variable definitions have been mapped to the ICD-10
[36] and SNOMED [37] dictionaries.
Ethics, data collection, and dissemination
All participating networks have obtained ethics/regula-
tory approval or the equivalent from their local granting
agencies to allow for de-identified data to be sent to the
iNeo Coordinating Centre at the Maternal-Infant Care
Research Centre, Mount Sinai Hospital, Toronto,
Canada. The Coordinating Centre has been granted Re-
search Ethics Board approval for the development, com-
pilation, and hosting of the iNeo dataset, and all
networks have signed data transfer agreements with the
iNeo Coordinating Centre. Privacy and confidentiality of
patient and unit-related data will be of prime importance
to the iNeo collaboration, and data collection, handling,
and transfer will be performed in accordance with the
Canadian Privacy Commissioners guidelines, the Per-
sonal Information Protection and Electronic Documents
Act, and any other local rules and regulations. No data
identifiable at the patient level will be collected or trans-
mitted, and only aggregate data will be reported. For all
stages of the project, participating units will be assigned
a code by their own network prior to data transfer into
the iNeo dataset so that units remain anonymous within
the iNeo collaborative. Following data analysis, findings
will be disseminated within networks by their own net-
work coordination team and not by the iNeo central
team.
Following completion of the study in 2017, the data
will be kept at the iNeo Coordinating Centre for a fur-
ther two years before being returned to the originating
networks unless otherwise agreed by the member
networks.

Table 1 Characteristics of networks participating in the International Network for Evaluating Outcomes of Neonates
(iNeo)
Network Australia and Canadian Israeli Neonatal Spanish Swedish Swiss Neonatal UK Neonatal
New Zealand Neonatal Neonatal Research Neonatal Neonatal Network & Collaborative
Neonatal Network Network Network Network Quality Follow-Up
Network Japan Register Group
Country Australia and Canada Israel Japan Spain Sweden Switzerland UK (England)
New Zealand
Level III NICUs 23 + 6 30 23 93 n/a 7 9 45
in the country
Level III NICUs 29 30 23 73 36 7 9 44
in the network
Number of inhabitants Australia: 23 million 34 million 7.9 million 126 million 47 million 9.5 million 8 million 52 million
NZ: 4.4 million
Number of births/year Australia: 300,000 380,863 166,000 1,071,304 497,023 110,000 80,000 687,000
NZ: 60,000
Number of eligible 3,500 2,700 1,500 3,700 2,600 900 800 7,700
NICU admissions/year
(<32 wks gestation/<1500 g)
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Comparisons of neonatal outcomes between networks
Outcomes
The primary outcome for comparison between the net-
works will be a composite indicator of mortality or any
of the four major neonatal morbidities (severe neuro-
logical injury, severe ROP, NEC, and BPD). Mortality
will be defined as death due to any cause prior to dis-
charge home. Severe neurological injury will be defined
as stage 3 intraventricular hemorrhage (IVH) with ven-
tricular dilatation according to the criteria of Papile
et al. [38], or parenchymal injury (including periven-
tricular leukomalacia) with or without IVH. Severe ROP
will be defined as stage 3 according to the International
Classification [39], or need for laser surgery or intraocu-
lar injections of anti-vascular endothelial growth factor
agents. NEC will be defined as stage 2 according to
Bells criteria [40] and BPD as oxygen requirement at
36 weeks post-menstrual age [41].
Secondary outcomes to be compared among iNeo mem-
ber networks will include the individual morbidities of the
composite outcome, as well as nosocomial infection de-
fined as culture-proven sepsis (blood or cerebrospinal
fluid positive for pathogenic organism) at >3 days or
72 hours postnatal age [42], patent ductus arteriosus re-
quiring pharmacological treatment and/or surgical
ligation, receipt of delivery room cardiopulmonary resus-
citation, air leak syndrome, and resource utilization
(length of stay and length of respiratory support). To ac-
count for potential differences in practices regarding dis-
charge home and transfer to Level 2 community units,
additional analyses will compare mortality by Day 28 after
birth. All outcomes will be expressed as ratios with the de-
nominator equal to all admissions to participating NICUs.
Adjustment for variations in baseline population
characteristics between networks
Demographic characteristics and severity of illness are
well known to impact neonatal outcomes [43] and are also
likely to vary between networks. To prevent bias, these
potential confounders will be controlled in analyses com-
paring network-level outcome rates. The common mini-
mum dataset includes important predictors, such as
gestational age, sex, plurality of pregnancy, and receipt of
antenatal corticosteroids, which will be used to adjust ana-
lyses as appropriate. In addition, most networks collect
various measures of severity of illness, such as CRIB [44],
SNAPPE-II [45], or TRIPS [46] scores. These will be stan-
dardized within each network (assigned a score between 0
and 1) and adjusted for in analyses.
Descriptive analyses of baseline factors
The distribution of infant characteristics and network-
level broad organizational structural features will be
summarized as counts and percentages for categorical
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variables and using the mean and standard deviation, or
the median and interquartile range for continuous vari-
ables. The data will be compared among all networks
using the Chi-square test for categorical and ANOVA
F-test or Moods median test for continuous variables.
Comparisons between networks
For the primary composite outcome, each of its compo-
nents and the additional secondary outcomes, initial
crude rates, and associated 95% and 99% confidence in-
tervals will be calculated and graphically displayed using
caterpillar plots to visually identify differences between
networks. To adjust for multiple baseline characteristics,
standardized outcome ratios will be computed using the
indirect standardization approach. Each networks ob-
served rate will be compared with the expected rate
based on the total sample from all other networks to
identify networks with rates significantly above or below
average. For each outcome, the expected number of
events will be computed as the sum of predicted prob-
abilities from a multivariable model (logistic regression
or zero inflated negative binomial models based on data
distribution) derived using data from all other networks
with adjustment for confounders. Network standardized
outcome ratios will be graphically displayed using fun-
nel plots with 95% and 99% prediction intervals for
comparison between networks.
A global comparison, as well as pair-wise comparisons
between networks, will be performed using multivariate
regression models adjusted for confounders. Statistical
models will employ generalized estimating equations to
adjust analyses for clustering of infants within networks.
In addition, hierarchical random-effects regression models
will be used to allow for variation at the network and unit
level. Statistical significance will be evaluated by applying
a Bonferroni correction to account for multiple pair-wise
comparisons.
Statistical power for outcome comparisons
With retrospective data from 251 NICUs collected over
four years (20072010), analyses (two-sided tests) com-
paring Canada (10,800 admissions) with all other net-
works (82,800 admissions), for example, will be able to
detect rate differences of 0.004 to 0.02 for a range of
outcome rates (1% to 40%) with statistical power of 80%
assuming 5% type I error rate. Similar analyses compar-
ing Canada with one other network (3,200 to 30,800 ad-
missions) will be able to detect rate differences of 0.007
to 0.03.
Association of site characteristics and practices with
outcomes
To identify factors contributing to outcome variation be-
tween networks, detailed information will be obtained
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on health service provision, including units physical lay-
out, environmental characteristics, human factors, and
management practices at the national and site level. The
type of data and strategy for collecting this information
will be determined following the comparison of out-
comes between networks to target identified problem
areas and evaluate the culture, context, and practices of
each network. Factors with possible impact on outcome
differences between and within networks will be ascer-
tained using a variety of tools, such as surveys, recurring
questionnaires, and in specific instances, site visits to ex-
plore details if permitted.
The data will be pooled across sites and networks, and
statistical analyses will identify factors significantly asso-
ciated with outcomes. Through a collaborative process,
findings will be discussed with members of participating
networks to select physical and environmental factors,
human and resource factors, or processes of care that
can be modified through a quality improvement process.
Each network will then implement practice changes
within these three main target areas according to their
outcome priorities and the constraints of their respective
health care systems.
Physical and environmental factors
For preterm infants, adaptation to the environment is
crucial for their survival, wellbeing, and development.
The physical environment of the NICU is significantly
different from the in-utero environment and contains a
wide range of sensory stimuli that a preterm infant
would not be exposed to if carried to term [47]. There
has been wide debate as to the optimal physical charac-
teristics of a NICU in relation to outcomes for VLBW
infants. Several units that have implemented a single in-
fant per room design in place of the more traditional
open multi-patient rooms have reported improvements
in outcomes, but impact on staff satisfaction and work-
efficiency remains unclear [48,49]. Higher physical de-
mands and workloads placed on nurses could negatively
affect the level of care provided. Additional key physical
characteristics include internal and external noise [50,51],
temperature control, exposure to light [52,53], practice of
developmentally supportive care [54], provision and extent
of family-centered care, provision and extent of breast-
feeding support, potential for continuous parental involve-
ment, as well as training and preparation for discharge
home.
Physical characteristics will be assessed by conducting a
snapshot survey of units within the iNeo networks. The
survey will be developed, piloted, and implemented in col-
laboration with the iNeo Scientific Advisory Committee
by iNeo researchers with experience investigating the
extraneous factors that may impact quality of care.
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Human and resource factors
Human factors and available resources represent another
aspect of care provision possibly associated with differ-
ences in outcomes. However, associations between hu-
man and resource factors and neonatal outcomes have
not been thoroughly investigated, particularly not on a
national scale. Human factors include staffing in relation
to day and night shifts [33,55], weekdays versus week-
ends [56], ratio of nurses to patients [57], pattern of
work for medical and nursing staff (hours on call, total
duration of active duty time over 4 week period, etc.),
number and types of trainee doctors, allied healthcare
personnel coverage, constitution of attending team for
high-risk births, and relative expertise of the health care
providers attending resuscitation of extremely preterm
infants considering their overall experience in direct pa-
tient care, training, and research.
Neonatal outcomes are also impacted by resource
availability and utilization, specifically volume and cap-
acity. Units with high volume are reported to have better
outcomes compared with units with low volume, pos-
sibly due to relatively increased staff experience [58,59];
however, it has also been noted that low volume units
may be less crowded and have reduced rates of compli-
cations [60]. Alternatively, these differences may be sec-
ondary to centralization of care rather than volume, as
seen in data from Finland [61]. Similarly, units function-
ing at >90% capacity at all times, irrespective of volume,
may have different outcomes compared with units oper-
ating at lower capacity.
Data on human factors and resource utilization will be
collected using snapshot surveys administered at the unit
level. Due to likely variations from year to year, data on
human factors and resource utilization will be collected
on an annual basis using electronic tools (such as recur-
ring auto-filled surveys based on previous responses so as
to only report changes), and while the data may not cap-
ture variation in the daily activity levels or acuity in the
unit, this will represent the average condition.
Care-provision factors
Clinical practices represent the third and possibly most
important set of characteristics that likely contribute to
variation in outcomes. Variations in clinical practices
are well known among neonatal communities [8]; how-
ever, no systematic prospective approach has determined,
compared, and benchmarked variations associated with
outcomes. Some of the key practice variations between
centers and networks include referral practices (inborn vs.
outborn) [62-64], differential use of the type of initial re-
spiratory support [65-67], types and timings of surfactant
administration [68], fluid management [69], timing of ini-
tiation of parenteral nutrition [70], use of donor milk,
management of patent ductus arteriosus [71], availability
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and use of echocardiography, use of prophylactic interven-
tions [72] (e.g., probiotics, high frequency oscillatory ven-
tilation, phototherapy, and L-arginine), and the scope of
involvement of parents.
Specific to each secondary outcome we will identify
top performing networks and networks with significant
room for improvement. Subsequently, working groups of
interested stakeholders from each network will be
formed to determine methods to identify possible care
provision practices related to such variations. Study
methods will be similar to those described earlier, and
will include annual snapshot surveys of each unit, de-
tailed questionnaires specific to practices (e.g. parental
presence, use of donor milk, diagnosis and management
of hypotension, etc.), and in certain instances of out-
standing success, a site visit with structured exploration
of the practices in question. All methods of exploration
will be conducted with directions from the iNeo Governing
Board and Scientific Advisory Committee to protect privacy
and confidentiality. Because individual unit information will
not be disclosed to the iNeo Coordinating Centre, individ-
ual networks will be asked to identify willing members for
such participation.
Statistical analyses and power for identification of practice
and service variation
Associations of clinical management practices and other
external factors with outcomes will be assessed under
the general framework of individual patient-level data
meta-analyses. Random-effects models with adjustment
for confounding variables and important risk factors will
provide estimates of association and quantify residual
variation due to unknown or unmeasured unit-specific
and network-level factors. These analyses will identify
treatment practices and health care services with signifi-
cant impact on outcomes, which subsequently can be
targeted for implementation or improvement by specific
units or networks. This information along with details of
the practices/factors will be made available to initiate
discussion within the iNeo community regarding data-
informed, evidence-linked potentially better practices.
Analyses (two-sided tests) based on 10,000 yearly admis-
sions evaluating impact of treatment/practices (assuming
50% exposure) on outcomes (incidence 1% to 40%) will
be able to detect relative risks of 1.6 to 1.1 with statis-
tical power of 80% and 5% type I error rate. This is a
conservative power calculation based on data expected
to be collected in a one-year timeframe.
Implementation and evaluation of practice changes to
improve outcomes
Practices identified as being associated with an improve-
ment in outcomes will be proposed to network sites for
implementation using the continuous cycle of application
Page 7 of 11
and evaluation central to the EPIQ method [34,35]. Qual-
ity improvement using EPIQ methodology has been im-
plemented in Canadian NICUs for the last 10 years. It is
based on three pillars: (1) the use of all available evidence
on a particular intervention from the published scientific
literature, (2) analysis of each institutes baseline data to
identify hospital-specific practices for targeted interven-
tion, and (3) the use of a network to share the results of
quality improvement for the purpose of collaborative
learning. The EPIQ method utilizes local context and al-
lows customization of interventions and implementation
strategies to maximize improvement potential at each in-
stitute. This is conducted in conjunction with leadership
and peer support from network members [34,35].
Our plan for the iNeo network is to expand the EPIQ
approach to an international level. We will advocate in-
corporation of several cycles of practice change imple-
mentation, evaluation, monitoring, and collaborative
learning within each unit over the course of two and a half
years. The online ViviWeb Virtual Research Community
(https://meta.cche.net/viviweb/default.asp) will be used to
facilitate collaboration between networks. Based on our
experiences and preliminary results implementing practice
changes in Canada, and following discussion with the
NRNJ, we anticipate that regular and productive dialogue
will significantly benefit many of the participating NICUs.
The practice changes implemented by individual units
within networks will be evaluated every 6 to 12 months
depending upon each centres capabilities to collect and
submit data. In addition to outcome indicators, process
indicators will be developed based on the specific inter-
ventions implemented. These indicators will measure
the short-term impact of practice change. For example,
an intervention targeting early surfactant administration
to reduce BPD will have process indicators for the time
of first surfactant administration and the proportion of
babies who received surfactant within the first 30 mi-
nutes after birth. The outcome of interest for this inter-
vention will be reduction in the incidence of BPD. Safety
and outcome improvements will be monitored within
each unit and network using control charts and Chi-
square tests for differences in outcome rates from base-
line. Multivariable logistic regression analyses will pool
data from units within each network to assess changes
in outcomes over time with adjustment for potential
confounders and important risk factors, and accounting
for clustering.
Long-term neurodevelopmental follow-up
The members of iNeo have agreed that while the present
initiative should focus on ascertaining outcomes prior to
discharge from the NICU, the longer-term goal should
be to assess and improve neurodevelopmental outcomes
of VLBW and VPT infants at two to three years of age.
Shah et al. BMC Pediatrics 2014, 14:110
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Presently, five networks (CNN, NRNJ, NDAU, SNN, and
ANZNN) follow and collect data from their infants up
to two to three years of age with one more network in
the planning stages of follow-up data collection (SNQ).
The remaining networks have expressed interest in
long-term follow-up, and will explore the possibility of
collecting these data. For available follow-up data, extra-
neous factors, and process of care factors during NICU
stay will be examined in relation to outcomes at two to
three years of age. A composite severe adverse outcome
will be defined as mortality or severe morbidity, includ-
ing non-ambulatory cerebral palsy, developmental indi-
ces more than two standard deviations below the mean,
legal blindness, or deafness requiring amplification. This
will require development of a follow-up dataset (similar
to the NICU minimum dataset) for the long-term neu-
rodevelopmental outcomes.
Secondary research questions
In order to foster a true international collaboration, the
data collected and housed at the iNeo Coordinating
Centre will be available to all iNeo member networks
and iNeo-affiliated investigators after the principal ana-
lyses are completed. The iNeo database will be available
to iNeo-affiliated investigators, including trainees, wish-
ing to examine new research questions/hypotheses.
Requests for data will need to be sent to the iNeo
Coordinating Centre for discussion and approval by the
iNeo Scientific Advisory Committee. In the initial stages
of the iNeo collaboration, analysis of the dataset in ques-
tion will be performed at the iNeo Coordinating Centre
and the results sent to the requesting investigator. In the
later stages, limited datasets may be released to an inves-
tigator using a secure electronic portal system. In all
publications, the final author will be the International
Network for Evaluating Outcomes of Neonates (iNeo).
For the analyses detailed in this protocol, the author list
will include representatives of all eight networks. For
additional projects, authors will be those individuals
who meet the criteria for authorship as laid out by the
ICJME. All publications will include a list of the member
networks in the acknowledgements.
Discussion
The iNeo collaboration will be the first multi-national
network to examine population-based data. Findings
from this international collaboration generated using ex-
tensive data will provide strong and novel evidence re-
garding practices contributing to outcome variation with
broad relevance to NICUs within iNeo and worldwide.
This is particularly true for the investigation of the en-
vironmental, human, and physical factors that impact
neonatal outcomes. The majority of current literature re-
lates to single center or regional experiences, whereas
Page 8 of 11
data from multiple national networks will provide robust
estimates that will allow development of unified recom-
mendations regarding optimal design and staffing of
neonatal units.
The nature of the information that will be generated
and the resources available within the collaborative will
put iNeo in a unique position to implement global
change to improve neonatal outcomes. Neonatal out-
comes and NICU care practices will likely vary signifi-
cantly between networks and there are many factors that
may underlie these variations. The initial findings from
the comparative analysis may not be welcomed by all
units, and recommendations for practice changes that
require extensive change or high financial input, such as
additional staff to attend births or changes to unit lay-
out, may be met with resistance. In answer to this, the
most persuasive element of the iNeo collaboration will
be the strength of the evidence produced from the data,
the pragmatic nature of the results, and higher degree of
statistical precision due to the large sample size.
In addition to the strength of the data, a high level of
collaboration between network members will provide a
mechanism to address barriers to change and ensure the
knowledge gained is effectively implemented to improve
neonatal outcomes. Working together we will ensure
that all factors that contribute to a target outcome are
identified and evaluated. Once identified, the process for
exploration of extraneous factors will be supervised by
the iNeo Director and Scientific Advisory Committee to
ensure that all suggested practice changes can be tai-
lored to networks depending on the presence or absence
of certain baseline covariates. Although the individual
network directors will be primarily responsible for driv-
ing change within their networks, iNeo will also provide
various activities and mechanisms to facilitate practice
change. This will include access to in-person and online
training, site visits between networks, effective dissemin-
ation of information, and liaison with policy makers in
member countries.
The iNeo collaboration will also act as a platform
whereby other NICUs and established networks or net-
works in the preliminary phase of development can access
evidence regarding impact of practices on outcomes,
and approaches for collaborative learning and prac-
tice improvement in neonatology. As such, initial
discussions with neonatal units in India, China, South
America, and Taiwan have been productive and these
networks are planning to assess and apply the results of
the iNeo collaboration.
In summary, the iNeo collaboration will serve as a
strong international platform for neonatal-perinatal
health services research in VLBW and VPT infants. The
evidence obtained using the iNeo platform will enable
clinical teams from member networks to identify,
Shah et al. BMC Pediatrics 2014, 14:110
http://www.biomedcentral.com/1471-2431/14/110
implement, and evaluate practice and service provision
changes aimed at improving the care and outcomes of
VLBW and VPT infants within their respective coun-
tries. The knowledge generated, assembly of expertise,
and pool of resources will be available worldwide with a
likely global impact.
Additional file
Additional file 1: iNeo data variables for collection with
explanatory notes. Description: List of the data variables that will be
collected and analyzed during the project described in the iNeo protocol.
Abbreviations
ANZNN: Australia-New Zealand Neonatal Network; BPD: Bronchopulmonary
dysplasia; CNN: Canadian Neonatal Network; EPIQ: Evidence-based Practice
for Quality Improvement; iNeo: International Network for Evaluating
Outcomes of Neonates; INN: Israel Neonatal Network; IVH: Intraventricular
hemorrhage; NEC: Necrotizing enterocolitis; NI: Nosocomial infection;
NICU: Neonatal intensive care unit; NRNJ: Neonatal Research Network of
Japan; SNN: Swiss Neonatal Network; SNQ: Swedish Neonatal Quality
Register: Neonatology; ROP: Retinopathy of prematurity; SEN1500: Spanish
Neonatal Network; UKNC: UK Neonatal Collaborative; VLBW: Very low birth
weight; VPT: Very preterm.
Competing interests
The authors declare that they have no competing interests.
Authors contributions
PSS conceived of the concept of iNeo, led the protocol design process, and
drafted the manuscript. LM designed the statistical analysis plan and
participated in the protocol design process. All the remaining authors (SKL,
KL, GS, RM, BR, SH, LSF, NM, MA, BD, MF, SK, RH) participated in network and
protocol design including reaching consensus on the minimum dataset, and
will direct the collection of data, dissemination of knowledge, and
implementation of practice changes within their respective networks. All
authors read, revised, and approved the final manuscript.
Acknowledgements
We would like to dedicate this protocol in memoriam to the late Adolf Valls
i Soler (19422013), a key contributor to the development of iNeo and the
protocol design. Prof. Valls i Soler was a respected leader of the Spanish
Neonatal Network and member of EuroNeoNet. We would also like to thank
Ruth Warre from the Maternal-Infant Care Research Centre for editorial
assistance. The Maternal-Infant Care Research Centre is supported by the
Ontario Ministry of Health and Long-Term Care.
Funding sources
Funding for iNeo has been provided by a Canadian Institutes of Health
Research Chair in Reproductive and Child Health Services and Policy
Research held by PSS. Additional organizational support is being provided by
the Maternal-Infant Care Research Centre, which is supported by the Ontario
Ministry of Health and Long-Term Care. The funding bodies played no role
in the study design; collection, analysis and interpretation of data; writing of
the manuscript; or the decision to submit the manuscript for publication.
Author details
1
Canadian Neonatal Network, Maternal-Infant Care Research Centre, Mount
Sinai Hospital, 700 University Avenue, Toronto, Ontario M5G 1X6, Canada.
2
Australia and New Zealand Neonatal Network, Royal Hospital for Women,
Level 2, McNevin Dickson Building, Sydney Childrens Hospital, Randwick,
NSW 2031, Australia. 3Swedish Neonatal Quality Register, Department of
Womens and Childrens Health, Uppsala University, 751 85 Uppsala, Sweden.
4
Neonatal Research Network Japan, Department of Health Policy, National
Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo
157-8535, Japan. 5Israeli Neonatal Network, Gertner Institute for
Epidemiology and Health Policy Research, Sheba Medical Centre, Tel
Hashomer 52621, Israel. 6Swedish Neonatal Quality Register, Department of
Page 9 of 11
Pediatrics, Umea University Hospital, SE-901 85 Ume, Sweden. 7Spanish
Neonatal Network, Unidad Neonatal Barakaldo, Plaza de cruces s/n, 5 Planta,
Unidad Neonatal, Barakaldo 48903, (Bizkaia), Spain. 8UK Neonatal
Collaborative, Imperial College London, Chelsea and Westminster Hospital
Campus, London SW10 9NH, UK. 9Swiss Neonatal Network, Division of
Neonatology, University Hospital Zurich, Frauenklinikstrasse 10, CH-8091
Zrich, Switzerland. 10Australia and New Zealand Neonatal Network,
University of Otago, Christchurch, 2 Riccarton Avenue, PO Box 4345,
Christchurch 8140, New Zealand. 11Neonatal Research Network Japan, Osaka
Medical Center and Research Institute for Maternal and Child Health, 840
Murodo-cho, Izumi, Osaka 594-1101, Japan. 12Neonatal Research Network
Japan, Maternal and Perinatal Center, Tokyo Womens Medical University, 8-1
Kawadacho, Shinjuku-ku, Tokyo 162-8666, Japan. 13Australia and New
Zealand Neonatal Network, Womens and Childrens Hospital, Adelaide, Level
2, McNevin Dickson Building, Sydney Childrens Hospital, Randwick, NSW
2031, Australia.
Received: 25 February 2014 Accepted: 5 March 2014
Published: 23 April 2014
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doi:10.1186/1471-2431-14-110
Cite this article as: Shah et al.: The International Network for Evaluating
Outcomes of very low birth weight, very preterm neonates (iNeo): a
protocol for collaborative comparisons of international health services
for quality improvement in neonatal care. BMC Pediatrics 2014 14:110.

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